Effects ofin VivoTreatment with Vasopressin and Analogues on Renal Adenylate Cyclase Responsiveness to Vasopressin Stimulationin Vitro*

Dose-dependent activation by vasopressin of renal adenylate cyclase was measured on medullo-papillary fractions obtained from rats which have an altered rate of endogeneous antidiuretic hormone (ADH) secretion. Rats were of the Brattleboro strain with hereditary hypothalamic diabetes insipidus and Wistar rats submitted to several treatments: water diuresis induced either by repeated water gastric loading of 7% of BW, or by drinking 5% glucose solution for two weeks; sodium chloride loading induced by giving 1.5% NaCl solution as a water source. Finally acute or chronic rises in blood antidiuretic activity up to pharmacological levels were obtained by im or iv administration of arginine-vasopressin (AVP) or other antidiuretic peptides, i.e., lysine-vasopressin (LVP), oxytoxin (OT) and the long acting vasopressin analogues, [l-deamino-8-D-arginine] vasopressin (DDAVP) and [6, l-β-deamino-cystathionine-8- D-arginine]vasopressin (DC6-DAVP). Reduction of ADH secretion in Brattleboro rats and in rats displaying induced water diuresis was accompanied by a 30% reduction of maximal adenylate cyclase activation by vasopressin in vitro. Sodium chloride loading or chronic administration of DDAVP induced a 30% increase in enzyme responsiveness to vasopressin. The effect of the DDAVP injected was only apparent when the animals were killed for membrane preparation at least 40 h after the final injection. Administration of pharmacological doses of vasopressin or analogues induced rapid and reversible reduction in adenylate cyclase responsiveness to vasopressin stimulation in vitro. An almost complete loss in enzyme response was obtained within 1 h but was completely reversed 24 h after treatment. The modifications observed were specific for vasopressin-sensitive activity (stimulation of the enzyme by sodium fluoride or 5′-guanylyl-imidodiphosphate was maintained). When comparing the relative abilities of neurohypophysial peptides to induce a decrease in enzyme responsiveness to vasopressin, the following order of potency was observed: AVP > LVP > OT. The long acting vasopressin analogues, DC6-DAVP and DDAVP, were found to be more potent than AVP.